Myeloid-Related Protein-14 Contributes to Protective Immunity in Gram-Negative Pneumonia Derived Sepsis

Abstract

Klebsiella (K.) pneumoniae is a common cause of pneumonia-derived sepsis. Myeloid related protein 8 (MRP8, S100A8) and MRP14 (S100A9) are the most abundant cytoplasmic proteins in neutrophils. They can form MRP8/14 heterodimers that are released upon cell stress stimuli. MRP8/14 reportedly exerts antimicrobial activity, but in acute fulminant sepsis models MRP8/14 has been found to contribute to organ damage and death. We here determined the role of MRP8/14 in K. pneumoniae sepsis originating from the lungs, using an established model characterized by gradual growth of bacteria with subsequent dissemination. Infection resulted in gradually increasing MRP8/14 levels in lungs and plasma. Mrp14 deficient (mrp14−/−) mice, unable to form MRP8/14 heterodimers, showed enhanced bacterial dissemination accompanied by increased organ damage and a reduced survival. Mrp14−/− macrophages were reduced in their capacity to phagocytose Klebsiella. In addition, recombinant MRP8/14 heterodimers, but not MRP8 or MRP14 alone, prevented growth of Klebsiella in vitro through chelation of divalent cations. Neutrophil extracellular traps (NETs) prepared from wildtype but not from mrp14−/− neutrophils inhibited Klebsiella growth; in accordance, the capacity of human NETs to kill Klebsiella was strongly impaired by an anti-MRP14 antibody or the addition of zinc. These results identify MRP8/14 as key player in protective innate immunity during Klebsiella pneumonia.

Human S100A9 potentiates IL‐8 production in response to GM‐CSF or fMLP via activation of a different set of transcription factors in neutrophils

“…S100A8 and S100A9 were also shown to be potent chemoattractants for neutrophils [10,27] and are important for host defense and clearance of various pathogens [28][29][30]. As IL-8 is one of the most potent chemoattractant for neutrophils and other leukocytes, data presented here suggest a new regulatory role for S100A9 by contributing to the secretion of this chemokine.…”

Neisseria gonorrhoeae Evades Calprotectin-Mediated Nutritional Immunity and Survives Neutrophil Extracellular Traps by Production of TdfH

“…(21,53,65). CP, through its Zn-chelating activity, was found to be the major antimicrobial component in NETs against Candida albicans, Klebsiella pneumoniae, and Aspergillus nidulans (27,30,66). Antimicrobial metal chelation in NETs can also be mediated by DNA itself (67).…”

Klebsiella pneumoniae: Going on the Offense with a Strong Defense

“…Once neutrophils are present in infected tissues, they employ the numerous effector functions in their arsenal to combat K. pneumoniae infection. Studies using both human neutrophils and mouse models of K. pneumoniae infection have noted the neutrophilic use of a number of processes to contain K. pneumoniae (22,(155)(156)(157)(158)(159)(160)(161)(162)(163)(164)(165)(166)(167)(168)(169)(170)(171). These processes include phagocytosis/opsonophagocytosis, the production of inflammatory cytokines, and the release of antimicrobial compounds and structures, such as reactive oxygen species, serine proteases (e.g., neutrophil elastase), lactoferrin, lipocalin-2, myeloperoxidase, and neutrophil extracellular traps (NETs), to contain the bacteria and mediate clearance (22,(155)(156)(157)(158)(159)(160)(161)(162)(163)(164)(165)(166)(167)(168)(169)(170)(171).…”